After the initial discovery of formoterol, it has enjoyed the attention of a good deal of research, attested by numerous publications that need not be detailed here as they are readily available to the art-skilled.
Formoterol has been used as a bronchodilator by its direct administration to the lungs of affected patients. In addition, a number of different means of administration have been detailed in the art, and for examples, there are cited U.S. Pat. Nos. 4,685,911, 4,879,119, 4,911,707 and U.S. Pat. No. 4,917,676 that address transdermal means of administration topically; U.S. Pat. No. 4,380,534 addressing a solid composition incorporating formoterol; U.S. Pat. No. 4,814,161 detailing a particular aerosol form; and U.S. Pat. No. 4,975,466 that discloses the topical administration of formoterol. The medical literature on formoterol is also extensive, detailing its use as a .beta.-adrenergic agonist bronchodilator.
A number of these literature references will be considered more particularly in respect of the present invention as they serve as a point of departure signalled by the new use of formoterol which is the predicate of the present invention.
Several studies reported in the literature provide findings consistent with formoterol manifesting an anti-edema effect. For example, formoterol inhibits the extravasation of Evans blue associated with passive cutaneous anaphylaxis in rats. Formoterol also has been reported to inhibit the increase in lung weight caused by the inhalation of histamine aerosol in guinea pigs. A recent study reports that pre-treatment of guinea pigs with aerosolized formoterol significantly reduces the amount of Evans blue extravasation into the trachea following exposure to histamine aerosol. Further, formoterol injected into the skin of normal humans reduces the size of wheals produced by intradermal injections of histamine. There are no known reports of the intravascular injection of formoterol for any related purpose.
A number of articles report on the inhibition of chemically-induced extravastion by terbutaline, a .beta.-adrenergic bronchodilator. For example, Arfors, et. al., Acta Physiol. Scand., Suppl 463 93 (I979) reports on the intravenous administration of terbutaline in reversing topically induced inflammation. Beets, et. al. Br. J. Pharmac. 70, 46(1980) similarly reports on the inhibition of drug-induced extravasation by intravenously administered terbutaline. Erjefalt, et. al., Agents and Actions 16, 9 (1985) report on the inhibition of capsaicin-induced inflammatory response in lower airways by measuring the microvascular effects of terbutaline given intravenously as a pre-treatment. See also the collective works of Svensjo, et. al., e.g., Agents and Actions 16, 19 (1985).
Contrary to the foregoing information with respect to terbutaline, Martling, et. al., Anesthesiology 68, 350 (1988) found that the selective intravenous administration of the .beta.-adrenergic agonist terbutaline did not significantly change the Evans blue extravasation in rat trachea. Further, the related compound albuterol failed to inhibit dye leakage at any dose studied, as reported by Boschetto, et. al., Am. Rev. Resoir. Dis. 139, 416 (I989) who obtained similar negative results after intravenous administration of albuterol. Boschetto, et. al., in explaining that their results were different from those earlier reported with terbutaline, state, without experimental support, that different routes of administration may be implicated.
Interestingly, Tokuyama, et. al., European Journal of Pharmacology 193, 35 (1991), found that inhaled formoterol aerosol inhibits histamine induced air flow obstruction and airway microvascular leakage and acknowledged that their results were in conflict with those of Boschetto, et. al., suggesting again that the different routes of administration may be implicated.
Tomioka, et. al. Arch. Int. Pharmacodyn 250, 279 (1981) bluntly stated that their results in rats of intravenously injected formoterol inhibiting passive cutaneous anaphylaxis, one manifestation of which is leaky blood vessels, are not due to a direct effect of the drug on vascular permeability. Indeed, in a later article by the same authors there is no mention of the anti-edema action of formoterol by any means. See Tomioka, et. al. Arch. Int. Pharmoacodyn, 267, 91 (1984).
The group of publications summarized above documents the disparity of the results of various experiments which have examined the possible anti-edema action of .beta.-adrenergic agonists, thus leaving an impression of unpredictability as to the relevance of such parameters as the effectiveness of each particular drug, the route of administration, the cause of the increased vascular permeability being treated, and the mechanism of any observed effects of the drug.